The Pi'spreclinical research program seeks to understand how activation of peripheral immune cells and central nervous system glia (microglia and astrocytes) triggers a cascade of events leading to neuronal activation, pathological pain states, and dysregulation of the clinically relevant effects of analgesic drugs. The current research focus is directly relevant to her long-term goals of understanding (a) immune-neural bi- directional interactions, and (b) pain modulation systems. The proposed project is a request for a K05 award for the PI to focus on programmatic investigations of pathological pain states. The currently funded projects include: (a) Immune/glial mediation of exaggerated pain states; NIDA K02 (Watkins PI; 6/03-5/08; DA015642); (b) Pain control via spinal interleukin-10 gene therapy; NIDA CEBRA Phase II (R01; Milligan PI; Watkins coPI; 09/04- 09/09; DA018156); (c) Pain facilitation via neuron-to-glia signaling; NIDA R01 (Watkins PI; 3/05-12/09; DA017670); (d) Opioid analgesics: modulation.of trigeminal & spinal glial activation; NIDCR R01 (Watkins PI; 7/06-4/11; DE017782); (e) Exploration of AV411, a blood brain barrier permeable glial activation inhibitor; Avigen (Watkins Pl;1/06-12/08); (f) Development of rat models to assess potential glial involvement in migraine; GlaxoSmithKline (Watkins PI; 1/07-12/09); (g) Translation from rats to humans: are chronic pain states in humans associated with glial activation in spinal cord and/or brain?; American Fibromyalgia Syndrome Association (Watkins CD Boulder PI; open ended small grant); (h) Human spinal cord glial cytokines & chronic pain NIAMSD R01 (Lorton, PI; Watkins, coPI; 7/07-6/12; AR054647); & (i) mRNA & protein analyses of spinal cord & CSF from spinal cord injury patients with vs without chronic pain; Craig Spinal Cord Injury Treatment & Rehabilitation Hospital (Watkins CU Boulder PI; 9/07-open ended small grant). In addition, projects under review include: (j) Development of opioid therapeutic approaches that fail to activate glia; Covidien (Watkins PI);(k) Exploring the potential of glia for regulating clinically relevant opioid actions, R01 proposal (Watkins PI);and (I) Exploiting viral mimicry to develop new therapies for treating neuropathic pain, R21 proposal (Leinwand PI; Watkins coPI). Thus this is an active & diverse research program exploring multiple levels of analyses at the forefront of pain research. All of these projects are focused on understanding immune/glial regulation of pain and analgesic actions. Beyond this extensive research program, the PI is committed to education of the scientific and lay communities on these topics via review articles and chapters and invited talks, and the mentorship of young investigators.